MAIDS is a retrovirus-induced immunodeficiency syndrome of mice characterized by progressive lymphoproliferation and immunodeficiency. The disease is dependent on expression in genetically susceptible mice of an unusual Gag protein encoded by a murine leukemia virus (MuLV). Induction and progression of disease are dependent on interactions of T cells and B cells with B cells being the primary target of infection. The current studies are focused on the characteristics of B cells needed to induce disease. Previously, we showed that CD19 and Vav-deficient mice were markedly impaired in development of MAIDS due to decreased replication of the causative virus. In contrast, CD22-deficient mice exhibited increased sensitivity. In a different approach, we addressed the question of whether the generation of germinal centers (GC) and GC B cells are a prerequisite for MAIDS using infection of mice deficient in TNFR1 or OCA-B. These animals normally exhibit impaired GC formation and immunoglobulin isotype switching. MAIDS developed normally in TNFR1-deficient mice but little evidence of disease was seen in OCA-B knockouts. B cells are not thus passive vessels for expression of the MAIDS defective virus, but require specific activation parameters for participation in disease. Recently, we have found that another mixture of MuLV, termed Rauscher-like MuLV,induces splenomegaly, lymphadenopathy and immmune dysfunction but with features quite distinct from MAIDS. This mixture does not contain a replication defective virus and the ecotropic virus seems to induce disease on its own. The unique ecotroic virus appears to be a recombinant that was induced in response to stimulation by alloantigens and events associated with multiple pregnancies. The mechanisms responsibel for the overlapping but distinct featuers of these two virus-induced syndromes are under investigation